Cognitive Symptoms in Schizophrenia Recognizing and Treating Cognitive Deficits in Schizophrenia

Psychiatric TimesPsychiatric Times Vol 26 No 6
Volume 26
Issue 6

Cognition” has more than one meaning. Cognitive-behavioral therapy refers to therapies that work on changing automatic thoughts and resulting schemas.

"Cognition” has more than one meaning. Cognitive-behavioral therapy refers to therapies that work on changing automatic thoughts and resulting schemas. When effective, cognitive therapy helps patients:

• Become aware of automatic thoughts

• Appreciate how these lead to schemas that distort global perception and limit one’s repertoire of responses

• Question and alter thoughts and schemas and thus achieve cognitive restructuring

A common metaphor for successful cognitive-behavioral therapy is that a patient comes in seeing the glass as “half empty” and leaves able to see that even “half-empty” glasses are simultaneously “half-full.”

In contrast, cognitive remediation, developed by neuropsychologists who initially used techniques for helping persons with traumatic brain injury, uses exercises-many computer-based-and other techniques to help patients with deficits in underlying processes that lead to disruptions in thinking. Cognitive remediation is focused not on distortions in global schemas but on neurocognitive processes that need to be either strengthened or bypassed by auxiliary pathways.

Pharmacotherapy for cognitive symptoms uses medications to correct dysfunctions in the processes that underlie thinking. Eventually, we will find ways to combine cognitive remediation with pharmacological interventions in treating cognitive symptoms in schizophrenia and other neuropsychiatric disorders.

An excellent operational definition for cognition as conceptualized in this article is that of Medalia and Revheim,1 2 leaders in the field of cognitive remediation. “Cognition refers to thinking skills, the intellectual skills that allow you to perceive, acquire, understand and respond to information. This includes the abilities to pay attention, remember, process information, solve problems, organize and reorganize information, communicate and act on information.”1(p5)

During the 1970s and 1980s, empirical work led researchers to propose that schizophrenia be seen as a disorder comprising more than one underlying process.2-4 In the 1990s, as pharmaceutical companies began marketing atypical antipsychotics as agents that improved negative as well as positive symptoms in addition to having fewer motor adverse effects, the concept of schizophrenia as a multidimensional disorder became widely accepted.5

Assessing cognition

Large-scale pharmaceutical company studies, along with investigator-initiated studies they inspired, frequently used 1 or more of the following symptom severity rating scales:

• The Scale for the Assessment of Negative Symptoms (SANS)6

• The Scale for the Assessment of Positive Symptoms (SAPS)7

• The Positive and Negative Syndrome Scale (PANSS)8

Large-scale studies provided data for SANS/SAPS and the PANSS-rated symptoms, which led to the approval of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole and allowed for factor analysis.

Factor analysis of the SANS/SAPS ratings revealed 3 factors: positive, negative, and disorganized symptoms. Factor analysis of the PANSS-rated symptoms revealed 5 factors: positive, negative, dysphoric mood, excitement/hostility (sometimes called activation), and cognitive (sometimes called autistic preoccupation) symptoms. For both SANS and SAPS, poor performance on neuropsychological tests was found to correlate with the negative and disorganized factors. Negative symptoms were related to poor performance on tests of verbal learning and memory, verbal fluency, visual memory, and visual-motor sequencing, while disorganized symptoms were correlated with lower verbal IQ and poor concept attainment.9

For the PANSS, poor performance on neuropsychological tests was found to correlate with the negative and the cognitive/autistic preoccupation factors, but not with severity of positive symptoms. In a study by Opler and colleagues,10 PANSS negative symptoms were found to be associated with difficulties in performing the Wisconsin Card Sorting Test (WCST), a measure of executive functioning and prefrontal integrity. Bell and colleagues11 found that the PANSS cognitive factor significantly correlated with poorer performance on all neuropsychological tests in a comprehensive battery that included the WCST.

Clearly, important questions remain to be answered about whether neurocognitive deficits are best conceptualized as correlates of negative and disorganized symptoms or whether they are a distinct independent feature. To the extent that neurocognitive deficits correlate with negative and disorganized symptoms, we also need to better understand how they are underlying contributors to these symptom dimensions.

The NIMH’s initiative, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), has jump-started the process for treating cognitive deficits in patients with schizophrenia. It has brought together experts and developed a consensus battery to be used by the FDA, and presumably other regulatory agencies, to evaluate the efficacy of new medications for the treatment of cognitive symptoms in schizophrenia.12 As shown in the Table, the resulting MATRICS Consensus Cognitive Battery consists of 10 tests that assess 7 cognitive domains.13

The role of neurochemical systems

Three neurochemical systems have emerged as potential targets for pharmacological agents: the cholinergic, D1 dopamine, and N–methyl D–aspartate (NMDA) glutamate systems. While not the only systems suggested and worthy of investigation, the consensus appears to be that these 3 offer the most promise.

In discussing these systems, rather than cataloguing ongoing or recently completed clinical trials, I focus on ways that practicing clinicians can begin to target these systems. Since there are no FDA-approved medications for the treatment of cognitive symptoms in schizophrenia, any suggested use of a presently available medication for treating cognitive symptoms in schizophrenia is by definition an off-label use. The off-label use of medications approved for other purposes is appropriate but needs to be evidence-based, discussed with the patient, and the best alternative.

Pharmacotherapy should be used with other psychosocial interventions. In the case of cognitive symptoms, combining pharmacotherapy with cognitive remediation, in addition to more traditional approaches, may lead to better quality of life and more rapid recovery.

The cholinergic system

In the 1970s, it was found that Alzheimer disease was caused primarily by the degeneration of acetylcholine (ACH) or cholinergic neurons that emanate from the nucleus basalis of Meynert. This landmark finding was on the one hand startling, since it had been thought that more widespread neurochemical deficits would be found. On the other hand, it was consistent with decades of work that showed that anticholinergic medications disrupted cognitive functions and, in particular, memory in nonpatient populations. Regarding schizophrenia, a small but compelling literature indicates that anticholinergics counter the therapeutic action of neuroleptics.14 Findings from recent clinical trials indicate that both muscarinic and nicotinic agonists hold promise in the treatment of cognitive symptoms of schizophrenia.15-16

While awaiting new cholinergic agonists, we can begin to address the cholinergic deficit in schizophrenia. First is to “do no harm” by avoiding the use of highly anticholinergic regimens that can exacerbate cognitive deficits. For example, if the use of anticholinergics to treat extrapyramidal syndrome (EPS) appears to be exacerbating cognitive symptoms, consider amantadine, which treats EPS but is not an anticholinergic. In a double-blind, cross-over study, Silver and Geraisy17 showed that biperiden (an anticholinergic), but not amantadine, interferes with memory and, in particular, visual memory.

It is extremely important to help those with schizophrenia to stop smoking; bear in mind, however, that they may smoke because nicotine improves their cognitive symptoms. While the smoking itself should cease, nicotine replacement therapy may need to be continued indefinitely to prevent a worsening of cognition.

D1 dopamine–mediated processes

A link has been shown between prefrontal dysfunction and the cognitive deficits observed in schizophrenia.18,19 Goldman–Rakic20 has suggested that disruption of D1 dopamine receptor activity can contribute to the cognitive symptoms of schizophrenia, while stimulation of the D1 dopamine receptor improves cognition.21

Modafinil has been found to improve short–term verbal memory span, visual memory, and spatial planning in patients with chronic schizophrenia. It is reasonable to hypothesize that it does this, at least in part, by stimulating D1 dopamine receptors.22

Hypofunction of the NMDAglutamate system

In the 1980s, phencyclidine (PCP), “angel dust,” was a widely used recreational drug of abuse. Some people were brought to psychiatric emergency departments with schizophrenia–like symptoms, including positive, negative, and cognitive symptoms. The hypothesis that schizophrenia may be a result of hypofunction of the NMDA glutamate system emerged when it was found that PCP blocked calcium efflux through channels controlled by NMDA glutamate receptors.

In the NMDA glutamate system, glutamate binding to a subset of receptors leads to the opening of the calcium channel, but only if a second site is simultaneously occupied by either glycine or D–serine, both of which are released into the synapse by astrocytes. Glycine’s action is terminated when it binds to a glycine transporter protein and is brought back to the astrocytes where it is oxidized. High doses of dietary glycine added to antipsychotic regimens can lead to clinical improvement, but in clinical practice, glycine–induced nausea limits its utility.23

Recently, another promising strategy has emerged. Glycine levels in the synapses can be raised by glycine transport inhibitors that prevent glycine from entering the surroundingastrocytes. Consequently, more glycine remains in the synapse.

Several glycine transport inhibitors are presently in or are entering clinical trials. One promising candidate is N–methylglycine, or sarcosine.24 Preliminary studies indicate that added to antipsychotics, 1 to 2 g of sarcosine per day can lead to significant improvement in positive, negative, and cognitive symptoms.


The next decade should bring new drugs that will treat cognitive symptoms in schizophrenia. While practicing clinicians wait for these new agents, this article suggests pharmacological agents and strategies that may improve cognitive symptoms in persons with schizophrenia.


Drugs Mentioned in This Article
Amantadine (Symmetrel)
Aripiprazole (Abilify)
Biperiden (Akinetone)
Modafinil (Provigil)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)

References1. Medalia A, Revheim N. Dealing With Cognitive Dysfunction Associated With Psychiatric Disabilities:A Handbook for Families and Friends of Individuals With Psychiatric Disorders.Albany, NY: New York State Office of Mental Health; 2002.
2. Strauss JS, Carpenter WT, Bartko JJ. The diagnosis and understanding of schizophrenia, III: speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull.1974;11:61–69.
3. Crow TJ. Molecular pathology of schizophrenia: more than one disease process? Br Med J.1980;280:66–68.
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5. Opler LA, Hwang MY. Schizophrenia: a multidimensional disorder. Psychiatr Ann.1994;24:491–495.
6. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS).Iowa City: The University of Iowa; 1983.
7. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS).Iowa City: The University of Iowa; 1984.
8. Kay SR, Opler LA, Fiszbein A. The Positive andNegative Syndrome Scale (PANSS) Manual.Toronto:Multi–Health Systems Inc; 2006.
9. O’Leary DS, Flaum M, Kesler ML, et al. Cognitive correlates of the negative, disorganized, and psychotic symptom dimensions of schizophrenia. J Neuropsychiatry Clin Neurosci.2000;12:4–15.
10. Opler LA, Ramirez PM, Rosenkilde CE, Fiszbein A. Neurocognitive features of chronic schizophrenic inpatients. J Nerv Ment Dis.1991;179:638–640.
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12. Buchanan RW, Davis M, Goff D, et al. A summary of the FDA–NIMH–MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull.2005;31:5–19.
13. Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry.2008;165:203–213.
14. Singh MM, Kay SR. A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics. Psychopharmacologia.1975;43:103–113.
15. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry.2008;165:1033–1039.
16. Freedman R, Olincy A, Buchanan RW, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry.2008;165:1040–1047.
17. Silver H, Geraisy N. Effects of biperiden and amantadine on memory in medicated chronic schizophrenic patients. A double–blind cross–over study. Br J Psychiatry.1995;166:241–243.
18. Merriam AE, Kay SR, Opler LA, et al. Neurological signs and the positive–negative dimension in schizophrenia. Biol Psychiatry.1990;28:181–192.
19. Wolkin A, Angrist B, Wolf A, et al. Low frontal glucose utilization in chronic schizophrenia: a replication study. Am J Psychiatry.1998;145:251–253.
20. Goldman–Rakic PS. The relevance of dopamine–d1 receptor in the cognitive symptoms of schizophrenia. Neuropsychopharmacology.1999;21:S170–S180.
21. Goldman–Rakic PS, Castner SA, Svensson TH,et al. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl).2004;174:3–16.
22. Turner DC, Clark L, Pomarol–Clotet E, et al. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology.2004;29:1363–1373.
23. Javitt DC, Zylberman I, Zukin SR, et al. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry.1994;151:1234–1236.
24. Tsai G, Lane HY, Yang P, et al. Glycine transporter I inhibitor, N–methylgycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry.2004;55:452–456.

Evidence–Based References
Javitt DC, Balla A, Sershen H, Lajtha A. A.E. Bennett Research Award. Reversal of phencyclidine–induced effects by glycine and glycine transport inhibitors.Biol Psychiatry.1999;45:668–679.
Nuechterlein KH, Barch DM, Gold JM, et al. Identification of separable cognitive factors in schizophrenia. Schizophr Res.2004;72:29–39.

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